Oral feeding of an immunodominant MHC donor-derived synthetic class I peptide prolongs graft survival of heterotopic cardiac allografts in a high-responder rat strain combination

The efficacy of two synthetic major histocompatibility complex (MHC)‐derived DA (RT1.Aa) 25‐mer peptides (residues 56–80 and 96–120) to modulate alloreactivity was tested in Lewis (RT1.A1) responder animals. The DA peptide 56–80, but not peptide 96–120, induced delayedtype hypersensitivity (DTH). DTH was significantly reduced by oral feeding of peptide 56–80, P = 0.004. In addition, oral feeding of this peptide in combination with a short course of cyclosporin A (CsA) prolonged graft survival of 60% of heterotope transplanted DA cardiac allografts in Lewis recipient rats. Long‐term survivors developed low levels of allo‐antibodies against donor tissue as compared to rejecting animals and increased levels of interleukin‐4 (IL‐4) within the allograft. Similarly, IL‐4‐secreting splenocytes were identified by flow cytometry in these animals, indicating a Th2‐type cytokine pattern. However, graft survival was particularly limited to cardiac allografts because donor‐type skin grafts were acutely rejected in tolerant animals. It is interesting that residue alignment of peptide 56–80 to the motif of the RT1.A1 molecule showed a preferred class I motif within this sequence, suggesting indirect presentation of this peptide to recipient T cells. Thus, peptide 56–80 appears to represent a dominant epitope that can be exploited for establishing tolerance in this transplantation strain combination. J. Leukoc. Biol. 67: 793–800; 2000.